At least eight progressive, inherited neurodegenerative disorders are caused by an expansion of the naturally occurring CAG tract that codes for a polyglutamine (polyQ) repeat within the coding region of the corresponding protein. These diseases include Huntington's disease (HD), spinal and bulbar muscular atrophy (SBMA; also known as Kennedy's disease), dentatorubral-pallidoluysian atrophy, spinocerebellar ataxia type 1 (SCA1), SCA2, SCA6, SCA7, and Machado-Joseph disease (MJD/SCA3)(Reddy et al. Trends Neuroscience 22:248–255, 1999). With the exception of SCA6 (CACNL1A4)(Zhuchenko et al. Nature 15:62–69, 1997), which is characterized by a minimal repeat expansion, affected individuals show a similar range of repeat expansion above ˜35 repeats (Kakizukca et al. Trends Genet. 14:396–402, 1998).
Each disorder is inherited as an autosomal dominant (or X-linked in the case of SBMA), neurological syndrome with selective, neuronal cell death resulting in distinct, but overlapping, clinical and pathological manifestations (Ross et al. Neuron 19:1147–1150, 1997). Age of onset is normally in mid-life; however, longer repeat ranges can cause more severe presentation of the disease with an earlier age of onset. Genetic studies provide evidence that inactivation of a single allele does not result in disease (Duyao et al. Science 269:407–410, 1995; Zeitlin et al. Nature Genet. 11:155–163, 1995). In addition, mouse models for HD, SCA-1 and MJD (Reddy et al. Trends Neuroscience 22:248–255, 1999; Burright et al. Cell 82:937–948, 1995; Hodgson et al. Neuron 23:181–192, 1999; Ikeda et al. Nature Genet. 13:196–202, 1996; and Mangiarini et al. Cell 87:493–506, 1996), carrying expanded repeat transgenes in a background with two normal alleles, show phenotypes resembling the corresponding disease suggesting a true dominant effect. The appearance of neuronal intranuclear inclusions that contain huntingtin and ubiquitin, in mice transgenic for exon 1 of huntingtin, implicates protein misfolding and aggregation as potential mediators of neuronal pathogenesis (Davies et al. Cell 90:537–548, 1997). These insoluble neuronal aggregates and nuclear inclusions have been described for many of the polyQ repeat diseases, having been seen in the affected regions of brains from patients (Kakizuka et al. Trends Genet. 14:396–402, 1998; DiFiglia et al. Science 277:1990–1993, 1997; Bates et al. Brain Pathol. 8:699–714, 1998; Paulson et al. Am. J. Hum. Genet. 64:339–345, 1999) and in most of the transgenic mouse models (Bates et al. Brain Pathol. 8:699–714, 1998; Paulson et al. Am. J. Hum. Genet. 64:339–345, 1999).
A role for nuclear localization of expanded polyQ repeat-containing disease proteins, independent of aggregation, has also been implicated in the initiation of disease and neurodegeneration (Klement et al. Cell 95:41–53, 1998; Saudou et al. Cell 95:55–66, 1998). In contrast, the presence of cytosolic aggregates in dystrophic neurites and neuropils in HD brain sections and in HD transgenic mice may reflect a pathogenic role for non-nuclear localization and aggregation (DiFiglia et al. Science 277:1990–1993, 1997; Gutekunst et al. J. Neurosci. 19:2522–2534, 1999; Li et al. Hum. Mol. Getter. 8:1227–1236, 1999). The aggregation phenomenon has been reproduced in vitro in a protein concentration and repeat length-dependent manner (Scherzinger et al. Proc. Natl. Acad. Sci. USA 96:4604–4609, 1999), demonstrating that aggregation is a property mediated by the expanded polyQ. The structure and behavior of polyQ repeats, both isolated and in protein contexts, have been examined in vitro; these studies argue that a structural transition associated with increased length occurs to mediate aggregation Perutz et al. Trends Biochem. Sci. 24:58–63, 1999).